1. Field of the Invention
The invention relates to methods of inducing anesthesia or conscious sedation by administration of benzodiazepines in combination with opiate analgesics.
2. Description of the Prior Art
Combinations of opiate analgesics, e.g., fentanyl or meperidine, and benzodiazepines such as diazepam and midazolam, are commonly administered prior to the performance of certain surgical and exploratory procedures, including, e.g., gastric endoscopies and colonoscopies. It has long been known that such combinations can induce respiratory depression, as can benzodiazepines administered alone by the intravenous route. It has also been known that opiates and benzodiazepines produce significant hypotension in many subjects when administered parenterally, although such hypotension is rarely life-threatening when each agent is administered independently.
Pure narcotic antagonists of the naloxone type are highly effective in reversing the untoward side effects of opiate analgesics, including hypotension. However, considerably higher doses of naloxone are required to antagonize opiate-induced hypotension than other opiate effects, probably because the hypotension is mediated in large measure through delta receptors (see, e.g. J. Holaday, et al., Life Sciences 31:2209-2212 (1982)) and naloxone is far more potent on the mu receptor (responsible for opiate analgesia and related effects) than the delta receptor (H. Fields, et al., Nature 284:351-353 (1980)).
Benzodiazepines produce hypotension by a completely different mechanism than opiates--i.e., by central inhibition of sympathetic outflow, with a significant decrease in systemic vascular resistence. Numerous studies demonstrate that both diazepam and midazolam produce modest hypotension when used at their recommended dosages. Benzodiazepines do not, however, bind to opioid receptors.
When benzodiazepines and opiate analgesics are administered in combination, there is often a far greater decrease in blood pressure and cardiac output than desired. In fact, this combination may produce a supraadditive effect on blood pressure.
While this effect has been observed with combinations such as diazepam and morphine (J. Marty, et al., Anesth. Analg., 65:113-119 (1986)), it is particularly severe in the case of opiates administered in combination with intravenous midazolam. Heikkila, et al. noted a decrease in mean arterial blood pressure of up to 32% in patients receiving the combination of intravenous midazolam and fentanyl (see Anesth. Analg., 66:693-696 (1987)). Moreover, a number of recently reported deaths after procedures such as colonoscopies are believed attributable to virtual circulatory collapse following meperidine/midazolam anesthesia.
The unusual feature of this severe fall of blood pressure is that it does not occur at the time of maximum blood levels of benzodiazepine and opiate, but it occurs most often after a substantial time delay when the plasma concentration of benzodiazedpine and opiate have fallen. Thus many subjects will have completed the surgical an diagnostic procedure and some may be released from observation before the circulatory collapse occurs. In one series of observations, the average time to circulatory collapse was 30 minutes post-procedure with several subjects having collapse occurring two to three hours post-procedure.
Although it is known that pure narcotic antagonists can reverse opiate-induced hypotension as well as, to some degree, benzodiazepine-induced hypotension, they have not been administered for the purpose of preventing or ameliorating the severe drop in blood pressure that can be caused by the administration of benzodiazepines in combination with opiates to induce anesthesia or conscious sedation. Any antagonist which may currently be administered following anesthesia with a benzodiazepine-opiate combination is normally intended to reverse sedation and possible respiratory depression, and the dosage level utilized is too small to prevent severe hypotension and possible circulatory collapse. For example, Nilsson, et al., Acta Anaesth. Scand.. 30:66-69 (1986) disclose the administration of naloxone subsequent to the induction of anesthesia with a midazolamfentanyl combination in patients undergoing abdominal surgery. But the patients received only 0.1-0.2 mg of naloxone intravenously, far too little to protect against the substantial fall in blood pressure which is often observed after the administration of such a combination.
While Nilsson, et al. claimed that they did not observe a major drop in blood pressure with their patients, this observation (if accurate) probably resulted from the fact that the procedures performed did not call for the type of preparation on the part of the patient, including purging and associated fluid loss, which is commonly called for in the case of colonoscopies and related procedures. It is in the latter cases that the most severe hypotensive episodes have occurred. In addition, the patients studied by Nilsson, et al. were ventilated with oxygen, which is often not the case when patients receive benzodiazepine-opiate combinations in situations where a trained anesthesiologist is not present.
At the present time, no truly safe method of inducing anesthesia or conscious sedation with benzodiazepine-opiate combinations has been developed, particularly in the case of patients undergoing colonoscopies or similar procedures where the risk of a sudden and severe drop in blood pressure after induction of anesthesia is not uncommon.